Impact of an active lifestyle on cardiovascular autonomic modulation and oxidative stress in males with overweight and parental history of hypertension.

Family history of hypertension is associated with early autonomic dysfunction and increased oxidative stress. These alterations have been found to be reinforced by the overweight factor. Conversely, an active lifestyle is effective in improving the mechanisms regulating blood pressure control. Hence, we ought to investigate the effects of an active lifestyle on the hemodynamic, autonomic and oxidative stress parameters in individuals carrying both family history of hypertension and overweight risk factors. Fifty-six normotensive males were divided into four groups: eutrophic offspring of normotensive parents (EN, n = 12), eutrophic and inactive with hypertensive parents (EH, n = 14), overweight and inactive with hypertensive parents (OH, n = 13), and overweight and physically active with hypertensive parents (OAH, n = 17). Cardiovascular autonomic modulation was assessed by heart rate (HRV) and blood pressure (BPV) variability indexes. Oxidative stress included pro/antioxidant markers and nitrite concentration. Inactive offspring of hypertensive parents (EH and OH) showed higher LFSBP (vs EN), an indicator of sympathetic outflow to the vasculature and reduced anti-oxidant activity (vs EN), while higher pro-oxidant markers were found exclusively in OH (vs EN and EH). Conversely, the OAH group showed bradycardia, higher vagally-mediated HFabs index (vs OH and EN), lower sympathovagal balance (vs OH) and preserved LFSBP. Yet, the OAH showed preserved pro/antioxidant markers and nitrite levels. Our findings indicates that overweight offspring of hypertensive parents with an active lifestyle have improved hemodynamic, cardiac autonomic modulation and oxidative stress parameters compared to their inactive peers.

Percepção de profissionais de enfermagem sobre o cuidado prestado ao neonato com estomia de eliminação intestinal / Percepción de profesionales de enfermería sobre el cuidado prestado al neonato con ostomía de eliminación intestinal / Nursing professionals' perceptions of the care provided to the neonate with intestinal elimination ostomy

Resumo Objetivos Conhecer a percepção da equipe de enfermagem da unidade neonatal sobre os cuidados prestados ao recém-nascido hospitalizado com estomia intestinal e discutir os fatores que interferem na assistência de enfermagem. Método Estudo exploratório, descritivo, com abordagem qualitativa. Participaram oito enfermeiros e oito técnicos de enfermagem que trabalham em uma Unidade Neonatal do Rio de Janeiro. Os dados foram coletados entre abril e junho de 2022, através de entrevista semiestruturada e análise de conteúdo. Resultados Emergiram duas categorias: "percepções da equipe de enfermagem quanto ao cuidar de recém-nascidos hospitalizados com estomias intestinais e a educação em saúde da família"; e "aspectos facilitadores e dificultadores da assistência de enfermagem ao recém-nascido com estomia intestinal e a importância da educação permanente no cenário da Unidade Neonatal". Conclusão e implicações para prática O manejo de neonatos com estomias intestinais é atual e implica em cuidados de enfermagem com o estoma e pele do recém-nascido, estendendo-se para a prática da educação em saúde dos familiares. É desafiador o manejo de complicações, a indisponibilidade de materiais e o cuidado fragmentado. Tal achado pode subsidiar o desenvolvimento de intervenções de enfermagem sistematizada para os recém-nascidos e seus pais na unidade neonatal.

Resumen Objetivos Conocer la percepción del equipo de enfermería de la unidad neonatal sobre el cuidado prestado al neonato hospitalizado con ostomías intestinales y discutir los factores que interfieren en el cuidado de enfermería. Método Estudio exploratorio, descriptivo, con abordaje cualitativo. Participaron ocho enfermeros y ocho técnicos de enfermería que actúan en una Unidad Neonatal de Rio de Janeiro. Datos colectados entre abril y junio de 2022, por entrevistas semiestructuradas y análisis de contenido. Resultados Emergieron dos categorías: "percepciones del equipo de enfermería sobre el cuidado al recién nacido hospitalizado con ostomías intestinales y la educación en salud de la familia"; y "aspectos que facilitan y dificultan el cuidado de enfermería al recién nacido con ostomía intestinal y la importancia de la educación continua en el ámbito de la Unidad Neonatal". Conclusión e implicaciones para la práctica El manejo de neonatos con ostomías intestinales es actual e implica cuidados de enfermería con el estoma y la piel del recién nacido, extendiéndose a la práctica de educación en salud para familiares. El manejo de complicaciones, la falta de materiales y la atención fragmentada son desafíos. Este hallazgo puede apoyar el desarrollo de intervenciones de enfermería sistematizadas para los recién nacidos y sus padres en la unidad neonatal.

Abstract Objectives To understand the perception of the nursing team of the neonatal unit about the care provided to hospitalized newborns with intestinal ostomy and to discuss the factors that interfere in nursing care. Method Exploratory and descriptive study, with a qualitative approach. Eight nurses and eight nursing technicians who work in a Neonatal Unit in Rio de Janeiro took part. Data were collected between April and June 2022, through semi-structured interviews and content analysis. Results Two categories emerged: "perceptions of the nursing team regarding the care of hospitalized newborns with intestinal ostomies and family health education"; and "facilitating and hindering aspects of nursing care for newborns with intestinal ostomy and the importance of continuing education in the setting of the Neonatal Unit". Conclusion and implications for practice The management of newborns with intestinal ostomies is current and involves nursing care with the stoma and skin of the newborn, extending to the practice of health education for family members. The management of complications, the unavailability of materials and fragmented care are challenging. This finding can support the development of systematized nursing interventions for newborns and their parents in the neonatal unit.

Protective role of cGAS in NASH is related to the maintenance of intestinal homeostasis.

BACKGROUND & AIMS: Various intracellular pathways regulate inflammation in NASH. Cyclic GMP-AMP synthase (cGAS) is a DNA sensor that activates STING and plays a role in inflammatory diseases. Here, we explored the role of cGAS in hepatic damage, steatosis, inflammation, and liver fibrosis in mouse models of NASH. METHODS: cGAS deficient (cGAS-KO) and STING deficient (STING-KO) mice received high fat-high cholesterol-high sugar diet (HF-HC-HSD) or relevant control diets. Livers were evaluated after 16 or 30 weeks. RESULTS: HF-HC-HSD diet, both at 16 and 30 weeks, resulted in increased cGAS protein expression as well as in increased ALT, IL-1ß, TNF-α and MCP-1 in wild-type (WT) mice compared to controls. Surprisingly, liver injury, triglyceride accumulation, and inflammasome activation were greater in HF-HC-HSD cGAS-KO compared to WT mice at 16 and to a lesser extent at 30 weeks. STING, a downstream target of cGAS was significantly increased in WT mice after HF-HC-HSD. In STING-KO mice after HF-HC-HSD feeding, we found increased ALT and attenuated MCP1 and IL-1ß expression compared to WT mice. Markers of liver fibrosis were increased in cGAS- and STING-KO mice compared to WT on HF-HC-HSD. We discovered that cGAS-KO mice had a significant increase in circulating endotoxin levels on HF-HC-HSD that correlated with changes in intestinal morphology which was exacerbated by HF-HC-HSD compared to WT mice. CONCLUSION: Our findings indicate that cGAS or STING deficiency exacerbate liver damage, steatosis, and inflammation in HF-HC-HSD diet-induced NASH, which might be linked to the disruption of the gut barrier.

Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation.

BACKGROUND AIMS: Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood. APPROACH RESULTS: We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH. These ex-ASC specks persist in circulation even after the cessation of alcohol use. Administration of alcohol-induced-ex-ASC specks in vivo in alcohol-naive mice results in sustained inflammation in the liver and circulation and causes liver damage. Consistent with the key role of ex-ASC specks in mediating liver injury and inflammation, alcohol binge failed to induce liver damage or IL-1ß release in ASC-deficient mice. Our data show that alcohol induces ex-ASC specks in liver macrophages and hepatocytes, and these ex-ASC specks can trigger IL-1ß release in alcohol-naive monocytes, a process that can be prevented by the NLRP3 inhibitor, MCC950. In vivo administration of MCC950 reduced hepatic and ex-ASC specks, caspase-1 activation, IL-1ß production, and steatohepatitis in a murine model of AH. CONCLUSIONS: Our study demonstrates the central role of NLRP3 and ASC in alcohol-induced liver inflammation and unravels the critical role of ex-ASC specks in the propagation of systemic and liver inflammation in AH. Our data also identify NLRP3 as a potential therapeutic target in AH.

Altered ethanol metabolism and increased oxidative stress enhance alcohol-associated liver injury in farnesoid X receptor-deficient mice.

BACKGROUND & AIMS: Pharmacological activation of farnesoid X receptor (FXR) ameliorates liver injury, steatosis and inflammation in mouse models of alcoholic liver disease (ALD), but the underlying mechanisms of the protective effect of FXR against ALD remain unclear. METHODS: To investigate the role of FXR in ALD, we used the NIAAA model of chronic plus binge ethanol feeding in FXR-deficient knockout (FXR KO) mice. RESULTS: Ethanol-mediated liver injury and steatosis were increased in FXR KO mice, while both WT and FXR KO mice consumed the same amount of alcohol. Ethanol feeding induced liver inflammation and neutrophil infiltration that were further increased in FXR KO mice. In addition, collagen accumulation and expression of profibrotic genes were markedly elevated in the liver of alcohol-fed FXR KO compared to wild-type mice, suggesting that ethanol-induced liver fibrosis is enhanced in the absence of FXR. Surprisingly, FXR KO mice showed reduced blood alcohol levels post-binge, while CYP2E1 and ALDH1A1 were upregulated compared to WT mice, suggesting that alcohol metabolism is altered in FXR KO mice. Notably, exacerbated liver injury in FXR KO mice was associated with increased oxidative stress. ALDH1A1 activity was upregulated in FXR-deficient mouse primary hepatocytes, contributing to reactive oxygen species (ROS) generation, in vitro. Finally, using an ALDH1A1 inhibitor, we showed that ALDH1A1 activity is a key contributor to alcohol-induced ROS generation in FXR-deficient hepatocytes, in vitro. CONCLUSION: ALD pathogenesis in FXR KO mice correlates with altered ethanol metabolism and increased oxidative stress, providing new insights into the protective function of FXR in ALD.

Granulocyte colony-stimulating factor attenuates liver damage by M2 macrophage polarization and hepatocyte proliferation in alcoholic hepatitis in mice.

Massive inflammation and liver failure are main contributors to the high mortality in alcohol-associated hepatitis (AH). In recent clinical trials, granulocyte colony-stimulating factor (G-CSF) therapy improved liver function and survival in patients with AH. However, the mechanisms of G-CSF-mediated beneficial effects in AH remain elusive. In this study, we evaluated effects of in vivo G-CSF administration, using a mouse model of AH. G-CSF treatment significantly reduced liver damage in alcohol-fed mice even though it increased the numbers of liver-infiltrating immune cells, including neutrophils and inflammatory monocytes. Moreover, G-CSF promoted macrophage polarization toward an M2-like phenotype and increased hepatocyte proliferation, which was indicated by an increased Ki67-positive signal colocalized with hepatocyte nuclear factor 4 alpha (HNF-4α) and cyclin D1 expression in hepatocytes. We found that G-CSF increased G-CSF receptor expression and resulted in reduced levels of phosphorylated ß-catenin in hepatocytes. In the presence of an additional pathogen-associated molecule, lipopolysaccharide (LPS), which is significantly increased in the circulation and liver of patients with AH, the G-CSF-induced hepatoprotective effects were abolished in alcohol-fed mice. We still observed increased Ki67-positive signals in alcohol-fed mice following G-CSF treatment; however, Ki67 and HNF-4α did not colocalize in LPS-challenged mice. Conclusion: G-CSF treatment increases immune cell populations, particularly neutrophil counts, and promotes M2-like macrophage differentiation in the liver. More importantly, G-CSF treatment reduces alcohol-induced liver injury and promotes hepatocyte proliferation in alcohol-fed mice. These data provide new insights into the understanding of mechanisms mediated by G-CSF and its therapeutic effects in AH.

Cell-to-Cell Communications in Alcohol-Associated Liver Disease.

This review covers some important new aspects of the alcohol-induced communications between liver parenchymal and non-parenchymal cells leading to liver injury development. The information exchange between various cell types may promote end-stage liver disease progression and involves multiple mechanisms, such as direct cell-to-cell interactions, extracellular vesicles (EVs) or chemokines, cytokines, and growth factors contained in extracellular fluids/cell culture supernatants. Here, we highlighted the role of EVs derived from alcohol-exposed hepatocytes (HCs) in activation of non-parenchymal cells, liver macrophages (LM), and hepatic stellate cells (HSC). The review also concentrates on EV-mediated crosstalk between liver parenchymal and non-parenchymal cells in the settings of HIV- and alcohol co-exposure. In addition, we overviewed the literature on the crosstalk between cell death pathways and inflammasome activation in alcohol-activated HCs and macrophages. Furthermore, we covered highly clinically relevant studies on the role of non-inflammatory factors, sinusoidal pressure (SP), and hepatic arterialization in alcohol-induced hepatic fibrogenesis. We strongly believe that the review will disclose major mechanisms of cell-to-cell communications pertained to alcohol-induced liver injury progression and will identify therapeutically important targets, which can be used for alcohol-associated liver disease (ALD) prevention.

Role of the Inflammasome in Liver Disease.

The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1ß, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on (a) signals and mechanisms of inflammasome activation, (b) the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and (c) potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation.

Cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension at rest and during orthostatic stress: role of the peripheral chemoreflex.

The baroreflex integrity in early-stage pulmonary arterial hypertension (PAH) remains uninvestigated. A potential baroreflex impairment could be functionally relevant and possibly mediated by enhanced peripheral chemoreflex activity. Thus, we investigated 1) the cardiac baroreflex in nonhypoxemic PAH; 2) the association between baroreflex indexes and peak aerobic capacity [i.e., peak oxygen consumption (V̇o2peak)]; and 3) the peripheral chemoreflex contribution to the cardiac baroreflex. Nineteen patients and 13 age- and sex-matched healthy adults (HA) randomly inhaled either 100% O2 (peripheral chemoreceptor inhibition) or 21% O2 (control session) while at rest and during a repeated sit-to-stand maneuver. Beat-by-beat analysis of R-R intervals and systolic blood pressure provided indexes of cardiac baroreflex sensitivity (cBRS) and effectiveness (cBEI). The PAH group had lower cBEI for all sequences (cBEIALL) at rest [means ± SD: PAH = 0.5 ± 0.2 vs. HA = 0.7 ± 0.1 arbitrary units (a.u.), P = 0.02] and lower cBRSALL (PAH = 6.8 ± 7.0 vs. HA = 9.7 ± 5.0 ms·mmHg-1, P < 0.01) and cBEIALL (PAH = 0.4 ± 0.2 vs. HA= 0.6 ± 0.1 a.u., P < 0.01) during the sit-to-stand maneuver versus the HA group. The cBEI during the sit-to-stand maneuver was independently correlated to V̇o2peak (partial r = 0.45, P < 0.01). Hyperoxia increased cBRS and cBEI similarly in both groups at rest and during the sit-to-stand maneuver. Therefore, cardiac baroreflex dysfunction was observed under spontaneous and, most notably, provoked blood pressure fluctuations in nonhypoxemic PAH, was not influenced by the peripheral chemoreflex, and was associated with lower V̇o2peak, suggesting that it could be functionally relevant.NEW & NOTEWORTHY Does the peripheral chemoreflex play a role in cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension (PAH)? Here we provide new evidence of cardiac baroreflex dysfunction under spontaneous and, most notably, provoked blood pressure fluctuations in patients with nonhypoxemic PAH. Importantly, impaired cardiac baroreflex effectiveness during provoked blood pressure fluctuations was independently associated with poorer functional capacity. Finally, our results indicated that the peripheral chemoreflex did not mediate cardiac baroreflex dysfunction among those patients.

Immunopathobiology and therapeutic targets related to cytokines in liver diseases.

Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma. The progression of liver disease is controlled by a variety of factors, including liver injury, inflammatory cells, inflammatory mediators, cytokines, and the gut microbiome. In the current review, we discuss recent data on a large number of cytokines that play important roles in regulating liver injury, inflammation, fibrosis, and regeneration, with a focus on interferons and T helper (Th) 1, Th2, Th9, Th17, interleukin (IL)-1 family, IL-6 family, and IL-20 family cytokines. Hepatocytes can also produce certain cytokines (such as IL-7, IL-11, and IL-33), and the functions of these cytokines in the liver are briefly summarized. Several cytokines have great therapeutic potential, and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases, which are also described.

The cardiovascular consequences of fatiguing expiratory muscle work in otherwise resting healthy humans.

In 11 healthy adults (25 ± 4 yr; 2 female, 9 male subjects), we investigated the effect of expiratory resistive loaded breathing [65% maximal expiratory mouth pressure (MEP), 15 breaths·min-1, duty cycle 0.5; ERLPm] on mean arterial pressure (MAP), leg vascular resistance (LVR), and leg blood flow ([Formula: see text]). On a separate day, a subset of five male subjects performed ERL targeting 65% of maximal expiratory gastric pressure (ERLPga). ERL-induced expiratory muscle fatigue was confirmed by a 17 ± 5% reduction in MEP (P < 0.05) and a 16 ± 12% reduction in the gastric twitch pressure response to magnetic nerve stimulation (P = 0.09) from before to after ERLPm and ERLPga, respectively. From rest to task failure in ERLPm and ERLPga, MAP increased (ERLPm = 31 ± 10 mmHg, ERLPga = 18 ± 9 mmHg, both P < 0.05), but group mean LVR and [Formula: see text] were unchanged (ERLPm: LVR = 0.78 ± 0.21 vs. 0.97 ± 0.36 mmHg·mL-1·min, [Formula: see text] = 133 ± 34 vs. 152 ± 74 mL·min-1; ERLPga: LVR = 0.70 ± 0.21 vs. 0.84 ± 0.33 mmHg·mL-1·min, [Formula: see text] = 160 ± 48 vs. 179 ± 110 mL·min-1) (all P ≥ 0.05). Interestingly, [Formula: see text] during ERLPga oscillated within each breath, increasing (∼66%) and decreasing (∼50%) relative to resting values during resisted expirations and unresisted inspirations, respectively. In conclusion, fatiguing expiratory muscle work did not affect group mean LVR or [Formula: see text] in otherwise resting humans. We speculate that any sympathetically mediated peripheral vasoconstriction was counteracted by transient mechanical effects of high intra-abdominal pressures during ERL.NEW & NOTEWORTHY Fatiguing expiratory muscle work in otherwise resting humans elicits an increase in sympathetic motor outflow; whether limb blood flow ([Formula: see text]) and leg vascular resistance (LVR) are affected remains unknown. We found that fatiguing expiratory resistive loaded breathing (ERL) did not affect group mean [Formula: see text] or LVR. However, within-breath oscillations in [Formula: see text] may reflect a sympathetically mediated vasoconstriction that was counteracted by transient increases in [Formula: see text] due to the mechanical effects of high intra-abdominal pressure during ERL.

Uncovering the mechanisms of exertional dyspnoea in combined pulmonary fibrosis and emphysema.

The prevailing view is that exertional dyspnoea in patients with combined idiopathic pulmonary fibrosis (IPF) and emphysema (CPFE) can be largely explained by severe hypoxaemia. However, there is little evidence to support these assumptions.We prospectively contrasted the sensory and physiological responses to exercise in 42 CPFE and 16 IPF patients matched by the severity of exertional hypoxaemia. Emphysema and pulmonary fibrosis were quantified using computed tomography. Inspiratory constraints were assessed in a constant work rate test: capillary blood gases were obtained in a subset of patients.CPFE patients had lower exercise capacity despite less extensive fibrosis compared to IPF (p=0.004 and 0.02, respectively). Exertional dyspnoea was the key limiting symptom in 24 CPFE patients who showed significantly lower transfer factor, arterial carbon dioxide tension and ventilatory efficiency (higher minute ventilation (V'E)/carbon dioxide output (V'CO2 ) ratio) compared to those with less dyspnoea. However, there were no between-group differences in the likelihood of pulmonary hypertension by echocardiography (p=0.44). High dead space/tidal volume ratio, low capillary carbon dioxide tension emphysema severity (including admixed emphysema) and traction bronchiectasis were related to a high V'E/V'CO2 ratio in the more dyspnoeic group. V'E/V'CO2 nadir >50 (OR 9.43, 95% CI 5.28-13.6; p=0.0001) and total emphysema extent >15% (2.25, 1.28-3.54; p=0.01) predicted a high dyspnoea burden associated with severely reduced exercise capacity in CPFEContrary to current understanding, hypoxaemia per se is not the main determinant of exertional dyspnoea in CPFE. Poor ventilatory efficiency due to increased "wasted" ventilation in emphysematous areas and hyperventilation holds a key mechanistic role that deserves therapeutic attention.

Epidemiological features, echocardiographic findings, and parasite load in patients with Chagas disease.

INTRODUCTION: Chagas disease is a major public health problem that is endemic in Brazil and Latin America. This study aimed to determine the socioeconomic, demographic, and clinical characteristics of 171 patients (mean age, 45 years; female, 65%) with Chagas disease at Hospital Universitário de Brasília, Federal District, Brazil. METHODS: We implemented this cross-sectional study using a clinical epidemiological questionnaire, electrocardiography, echocardiography, and quantitative detection of Trypanosoma cruzi DNA in blood using qRT-PCR. RESULTS: Among the patients, 26.3% had a full elementary education, and 13.2% were illiterate. Most (63.6%) were economically classified as class C, and 51.5% were born in Bahia state. A total of 62.0% participants reported previous contact with the triatomine bug. The clinical forms of the disease were indeterminate (69.51%), cardiac (15.24%), digestive (10.37%), and mixed (4.88%). The most common electrocardiographic abnormality was complete right bundle branch block in association with a divisional anterosuperior block. Only 14.6% of the patients complied with benznidazole medication for at least 60 days, and 164 of them were assessed by echocardiography. The parasite load was positive in 56% of the patients. CONCLUSIONS: Chagas disease affected mostly women, with the indeterminate chronic form of the disease.

Carotid chemoreflex activity restrains post-exercise cardiac autonomic control in healthy humans and in patients with pulmonary arterial hypertension.

KEY POINTS: Dysfunction of post-exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases. The afferent mechanisms that regulate the post-exercise cardiac autonomic control remain unclear. We found that afferent signals from carotid chemoreceptors restrain the post-exercise cardiac autonomic control in healthy adults and patients with pulmonary arterial hypertension (PAH). Patients with PAH had higher carotid chemoreflex sensitivity, and the magnitude of carotid chemoreceptor restraint of autonomic control was greater in patients with PAH as compared to healthy adults. The results demonstrate that the carotid chemoreceptors contribute to the regulation of post-exercise cardiac autonomic control, and suggest that the carotid chemoreceptors may be a potential target to treat post-exercise cardiac autonomic dysfunction in patients with PAH. ABSTRACT: Dysfunction of post-exercise cardiac autonomic control predicts mortality, but its underlying mechanisms remain unclear. We tested whether carotid chemoreflex activity restrains post-exercise cardiac autonomic control in healthy adults (HA), and whether such restraint is greater in patients with pulmonary arterial hypertension (PAH) who may have both altered carotid chemoreflex and altered post-exercise cardiac autonomic control. Twenty non-hypoxaemic patients with PAH and 13 age- and sex-matched HA pedalled until 90% of peak work rate observed in a symptom-limited ramp-incremental exercise test. Recovery consisted of unloaded pedalling for 5 min followed by seated rest for 6 min. During recovery, subjects randomly inhaled either 100% O2 (hyperoxia) to inhibit the carotid chemoreceptor activity, or 21% O2 (normoxia) as control. Post-exercise cardiac autonomic control was examined via heart rate (HR) recovery (HRR; HR change after 30, 60, 120 and 300 s of recovery, using linear and non-linear regressions of HR decay) and HR variability (HRV; time and spectral domain analyses). As expected, the PAH group had higher carotid chemosensitivity and worse post-exercise HRR and HRV than HA. Hyperoxia increased HRR at 30, 60 and 120 s and absolute spectral power HRV in both groups. Additionally, hyperoxia resulted in an accelerated linear HR decay and increased time domain HRV during active recovery only in the PAH group. In conclusion, the carotid chemoreceptors restrained recovery of cardiac autonomic control from exercise in HA and in patients with PAH, with the restraint greater for some autonomic indexes in patients with PAH.

Ischemic preconditioning boosts post-exercise but not resting cardiac vagal control in endurance runners.

PURPOSE: High cardiac vagal control in endurance athletes has been generally associated with adequate recovery from training and readiness to cope high-intensity training. A method that improves cardiac vagal control in endurance athletes could therefore be advantageous. Accordingly, we sought to test whether ischemic preconditioning (IPC) could enhance cardiac vagal control in endurance runners. METHODS: Fifteen subjects underwent IPC, sham ultrasound (SHAM) or control (CT), in random order. Subjects were informed both IPC and SHAM would be beneficial vs. CT (i.e., similar placebo induction), and IPC would be harmless despite ischemia sensations (i.e., nocebo avoidance). Resting cardiac vagal control was assessed via respiratory sinus arrhythmia (RSA) and heart rate variability (HRV) indexes. Post-exercise cardiac vagal control was assessed via heart rate recovery [HR time constant decay (T30) and absolute HR decay (HRR30s)] during 30-s breaks of a discontinuous incremental test. Capillary blood samples were collected for lactate threshold identification. RESULTS: RSA and HRV were similar among interventions at pre- and post-intervention assessments. Lactate threshold occurred at 85 ± 4% of maximal effort. T30 was similar among interventions, but IPC increased HRR30s at 70% and 75% of maximal effort vs. SHAM and CT (70%: IPC = 31 ± 2 vs. SHAM = 26 ± 3 vs. CT = 26 ± 2 bpm, mean ± SEM, P < 0.01; 75%: IPC = 29 ± 2 vs. SHAM = 25 ± 2 vs. CT = 24 ± 2 bpm, P < 0.01). CONCLUSION: IPC did not change resting cardiac vagal control, but boosted fast post-exercise cardiac vagal reactivation at exercise intensities below lactate threshold in endurance runners.

Macrophage-Specific Hypoxia-Inducible Factor-1α Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis.

Inflammatory cell activation drives diverse cellular programming during hepatic diseases. Hypoxia-inducible factors (HIFs) have recently been identified as important regulators of immunity and inflammation. In nonalcoholic steatohepatitis (NASH), HIF-1α is upregulated in hepatocytes, where it induces steatosis; however, the role of HIF-1α in macrophages under metabolic stress has not been explored. In this study, we found increased HIF-1α levels in hepatic macrophages in methionine-choline-deficient (MCD) diet-fed mice and in macrophages of patients with NASH compared with controls. The HIF-1α increase was concomitant with elevated levels of autophagy markers BNIP3, Beclin-1, LC3-II, and p62 in both mouse and human macrophages. LysMCre HIFdPA fl/fl mice, which have HIF-1α levels stabilized in macrophages, showed higher steatosis and liver inflammation compared with HIFdPA fl/fl mice on MCD diet. In vitro and ex vivo experiments reveal that saturated fatty acid, palmitic acid (PA), both induces HIF-1α and impairs autophagic flux in macrophages. Using small interfering RNA-mediated knock-down and overexpression of HIF-1α in macrophages, we demonstrated that PA impairs autophagy via HIF-1α. We found that HIF-1α mediates NF-κB activation and MCP-1 production and that HIF-1α-mediated impairment of macrophage autophagy increases IL-1ß production, contributing to MCD diet-induced NASH. Conclusion: Palmitic acid impairs autophagy via HIF-1α activation in macrophages. HIF-1α and impaired autophagy are present in NASH in vivo in mouse macrophages and in human blood monocytes. We identified that HIF-1α activation and decreased autophagic flux stimulate inflammation in macrophages through upregulation of NF-κB activation. These results suggest that macrophage activation in NASH involves a complex interplay between HIF-1α and autophagy as these pathways promote proinflammatory overactivation in MCD diet-induced NASH.

Epidemiological features, echocardiographic findings, and parasite load in patients with Chagas disease

Abstract INTRODUCTION Chagas disease is a major public health problem that is endemic in Brazil and Latin America. This study aimed to determine the socioeconomic, demographic, and clinical characteristics of 171 patients (mean age, 45 years; female, 65%) with Chagas disease at Hospital Universitário de Brasília, Federal District, Brazil. METHODS We implemented this cross-sectional study using a clinical epidemiological questionnaire, electrocardiography, echocardiography, and quantitative detection of Trypanosoma cruzi DNA in blood using qRT-PCR. RESULTS Among the patients, 26.3% had a full elementary education, and 13.2% were illiterate. Most (63.6%) were economically classified as class C, and 51.5% were born in Bahia state. A total of 62.0% participants reported previous contact with the triatomine bug. The clinical forms of the disease were indeterminate (69.51%), cardiac (15.24%), digestive (10.37%), and mixed (4.88%). The most common electrocardiographic abnormality was complete right bundle branch block in association with a divisional anterosuperior block. Only 14.6% of the patients complied with benznidazole medication for at least 60 days, and 164 of them were assessed by echocardiography. The parasite load was positive in 56% of the patients. CONCLUSIONS: Chagas disease affected mostly women, with the indeterminate chronic form of the disease.

LPS Induces mTORC1 and mTORC2 Activation During Monocyte Adhesion.

Monocyte adhesion is a crucial step in transmigration and can be induced by lipopolysaccharide (LPS). Here, we studied the role of mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, and PKC in this process. We used THP-1 cells, a human monocytic cell line, to investigate monocyte adhesion under static and flow conditions. We observed that 1.0 µg/mL LPS increased PI3K/mTORC2 pathway and PKC activity after 1 h of incubation. WYE-354 10-6 M (mTORC2/mTORC1 inhibitor) and 10-6 M wortmannin avoided monocyte adhesion in culture plates. In addition, WYE also blocked LPS-induced CD11a expression. Interestingly, rapamycin and WYE-354 blocked both LPS-induced monocyte adhesion in a cell monolayer and actin cytoskeleton rearrangement, confirming mTORC1 involvement in this process. Once activated, PKC activates mTORC1/S6K pathway in a similar effect observed to LPS. Activation of the mTORC1/S6K pathway was attenuated by 10-6 M U0126, an MEK/ERK inhibitor, and 10-6 M calphostin C, a PKC inhibitor, indicating that the MEK/ERK/TSC2 axis acts as a mediator. In agreement, 80 nM PMA (a PKC activator) mimicked the effect of LPS on the activation of the MEK/ERK/TSC2/mTORC1/S6K pathway, monocyte adhesion to ECV cells and actin cytoskeleton rearrangement. Our findings show that LPS induces activation of mTOR complexes. This signaling pathway led to integrin expression and cytoskeleton rearrangement resulting in monocyte adhesion. These results describe a new molecular mechanism involved in monocyte adhesion in immune-based diseases.

Patients with Impaired Descending Nociceptive Inhibitory System Present Altered Cardiac Vagal Control at Rest.

BACKGROUND: Patients with chronic musculoskeletal pain have a higher chance of presenting impairment in cardiovascular autonomic modulation, which may have implications for cardiovascular events. The autonomic nervous system plays an important role in pain modulation. However, it is unclear whether patients with inefficient descending nociceptive inhibition have poorer cardiovascular autonomic modulation. OBJECTIVE: To compare the cardiovascular autonomic modulation of patients with musculoskeletal pain who had normal versus impaired functioning of descending nociceptive inhibitory system (DNIS). STUDY DESIGN: A cross-sectional study. SETTING: Physiotherapy outpatient service. METHODS: Fifty-six patients with musculoskeletal pain were included. Conditioned pain modulation was assessed by the difference of algometric values held in the dorsal forearm and tibialis anterior muscle, before and after a thermal pain stimulus was employed via the cold pressure test (CPT). Patients with inefficient DNIS in both sites were classified as impaired responders (n = 14). The others were classified as normal responders (n = 42). Cardiac autonomic modulation was monitored at rest by heart rate variability (HRV). The blood pressure response to the CPT was used as a proxy of sympathetic responsiveness. RESULTS: Most of the patients were women (60%) and had chronic pain (75%). The groups had similar demographic characteristics. Patients with impaired DNIS showed lower HRV [RMSSD (P = 0.020), SDRR (P = 0.009), HF (ms2) (P = 0.027), LF (ms2) (P = 0.004), and total power (P = 0.002)]. The blood pressure response to CPT was similar between groups (systolic pressure, P = 0.813; diastolic pressure, P = 0.709). LIMITATION: Physical activity level, emotional changes, and visceral pathologies can alter the autonomic nervous system and may represent potential confounders. The low number of patients may have biased the results. CONCLUSION: Patients with impaired DNIS presented lower resting HRV, indicating an altered vagal control of the heart. In contrast, the blood pressure response to a sympathoexcitatory stimulus was preserved.The study was approved by the Research Ethics Committee of Augusto Motta University Centre (CAAE number: 46245215.9.0000.5235), and all patients signed the Informed Consent Form. KEY WORDS: Musculoskeletal pain, autonomic nervous system, heart rate, chronic pain, diffuse noxious inhibitory control, blood pressure, sympathetic nervous system, parasympathetic nervous system.